title: Synthesis and biochemical studies of 7-substituted 4,6-androstadiene-3,17-diones as aromatase inhibitors.
abstract: Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful as therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. Several 7 alpha-thio-substituted androstenediones have proven to be potent inhibitors of aromatase in vitro and in vivo. Recent research efforts have focused on designing aromatase inhibitors with both substitution at C-7 and extended linear conjugation in rings A and B of the steroid nucleus. The targeted compounds, 7-substituted 4,6-androstadiene-3,17-diones 4-10, were prepared by the addition of either Grignard or lithium reagents to 3,3:17,17-bis(ethylenedioxy)-5-androsten-7-one (3). Inhibitory activities of the compounds were evaluated in vitro by enzyme kinetic studies employing the microsomal fraction isolated from human term placenta. 7-Benzyl- and 7-phenethyl-4,6-androstadiene-3,17-dione analogues are effective inhibitors with apparent Ki's of 60.9-174 nM, while the 7-phenyl analogue exhibited an apparent Ki of 1.424 microM. Thus, several 7-substituted 4,6-androstadiene-3,17-diones were prepared and exhibited good competitive inhibition of aromatase in vitro in human placental microsomes.
authors.affiliation: College of Pharmacy, Ohio State University, Columbus 43210.
authors.forename: P K
authors.initials: PK
authors.lastname: Li
authors.forename: R W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000730:Androstadienes / Q000138:chemical synthesis / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors